New azolidinediones and thiadiazolidinediones as antihyperglycemic agents

ABSTRACT

This invention relates to novel compounds which have demonstrated oral antihyperglycemic activity in diabetic ob/ob and db/db mice, animal models on non-insulin dependent diabetes mellitus (NIDDM ot Type II diabetes). These compounds have the formula: ##STR1## wherein: R 1  is C 1  -C 6  alkyl, C 3  -C 8  cycloalkyl, thienyl, furyl, pyridyl, ##STR2##  where R 10  is hydrogen, C 1  -C 6  alkyl, fluorine, chlorine, bromine, iodine, C 1  -C 6  alkyoxy, trifluoroalkyl or trifluoroalkoxy; 
     R 2  is hydrogen or C 1  -C 6  alkyl; 
     X is O or S; 
     n is 0, 1, or 2; 
     A is ##STR3## where R 3  is hydrogen, C 1  -C 6  alkyl, halogen, C 1  -C 6  alkoxy, trifluoroalkyl or trifluoroalkoxy; 
     B is ##STR4## where R 4  is hydrogen, C 1  -C 6  alkyl, allyl, C 6  -C 10  aryl, C 6  -C 10  aryl-(CH 2 ) 1-6  --, fluorine, chlorine, bromine, iodine, trimethylsilyl or C 3  -C 8  cycloalkyl; 
     R 5  is hydrogen, C 1  -C 6  alkyl, C 6  -C 10  aryl, or C 6  -C 10  aryl-(CH 2 ) 1-6  --; 
     m is 0, 1, or 2; 
     R 6  is hydrogen or C 1  -C 6  alkyl; 
     R 7  is hydrogen or C 1  -C 6  alkyl; 
     R 8  and R 9  are selected independently from hydrogen, C 1  -C 6  alkyl, fluorine, chlorine, bromine, or iodine; 
     Y is S; 
     Z is N or CH; 
     or a pharmaceutically acceptable salt thereof.

This application is a continuation in part of U.S. patent applicationSer. No. 08/421,167 filed Apr. 13, 1995 which is a division of U.S.patent application Ser. No. 08/245,734 filed on May 18, 1994, now U.S.Pat. No. 5,468,762.

This invention relates to novel azolidines of Formula I below which havedemonstrated oral antihyperglycemic activity in diabetic db/db and ob/obmice, animal models of non-insulin dependent diabetes mellitus (NIDDM orType II diabetes). The Formula I compounds or pharmaceuticalcompositions thereof are therefore useful in treating hyperglycemia inmammals having non-insulin dependent diabetes mellitus.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a syndrome characterized by abnormal insulinproduction, increased urinary output and elevated blood glucose levels.There are two major subclasses of diabetes mellitus. One is theinsulin-dependent diabetes mellitus (IDDM or Type I), formerly referredto as juvenile onset diabetes since it was evident early in life, andnon-insulin dependent diabetes mellitus (NIDDM or Type II), oftenreferred to as maturity-onset diabetes. Exogenous insulin by injectionis used clinically to control diabetes but suffers from severaldrawbacks. Insulin is a protein and thus cannot be taken orally due todigestion and degradation but must be injected. It is not alwayspossible to attain good control of blood sugar levels by insulinadministration. Insulin resistance sometimes occurs requiring muchhigher doses of insulin than normal. Another shortcoming of insulin isthat while it may control hormonal abnormalities, it does not alwaysprevent the occurrence of complications such as neuropathy, retinopathy,glomerulosclerosis, or cardiovascular disorders.

Orally effective antihyperglycemic agents are used to reduce bloodglucose levels and to reduce damage to the nervous, retinal, renal orvascular systems through mechanisms affecting glucose metabolism. Suchagents act in a variety of different mechanisms including inhibition offatty acid oxidation, α-glycosidase inhibition, antagonism of α₂-receptors and inhibition of gluconeogenesis. Two classes of compoundshave predominated: the biguanides as represented by phenformin and thesulfonylureas as represented by tolbutamide (Orinase®). A third class ofcompounds which has shown antihyperglycemic activity arethiazolidinediones of which ciglitazone is the prototype. Ciglitazonesuppresses the symptoms of diabetes--hyperglycemia, hypertriglyceridemiaand hyperinsulinemia [Diabetes 32, 804-10 (1983)]. ##STR5##

Still another class of antihyperglycemic agents are theN-arylalkyl-N-hydroxy ureas and the2-(arylalkyl)-[1,2,4]oxadiazolidine-3,5-diones. The published PCT patentapplication WO 92/03425 discloses compounds of the formula: ##STR6##where R¹ and R² are independently H, C₁ -C₉ alkyl, C₃ -C₇ cycloalkyl,phenyl, etc. or R¹ and R² together are carbonyl, which have utility ashypoglycemic or hypocholesteremic agents.

The hypoglycemic properties of these compounds in ob/ob mice arediscussed by Goldstein et al. J. Med. Chem. 36, 2238-2240 (1993).

SUMMARY OF THE INVENTION

The novel compounds useful in the treatment of hyperglycemia arerepresented by the following formula: ##STR7## wherein: R¹ is C₁ -C₆alkyl, C₃ -C₈ cycloalkyl, thienyl, furyl, pyridyl, ##STR8## where R¹⁰ ishydrogen, C₁ -C₆ alkyl, fluorine, chlorine, bromine, iodine, C₁ -C₆alkyoxy, trifluoroalkyl or trifluoroalkoxy;

R² is hydrogen or C₁ -C₆ alkyl;

X is O or S;

n is 1 or 2;

A is ##STR9## where R³ is hydrogen, C₁ -C₆ alkyl, halogen, C₁ -C₆alkoxy, trifluoroalkyl or trifluoroalkoxy;

B is ##STR10## where R⁴ is hydrogen, C₁ -C₆ alkyl, allyl, C₆ -C₁₀ aryl,C₆ -C₁₀ aryl-(CH₂)₁₋₆ --, fluorine, chlorine, bromine, iodine,trimethylsilyl or C₃ -C₈ cycloalkyl;

R⁵ is hydrogen, C₁ -C₆ alkyl, C₆ -C₁₀ aryl, or C₆ -C₁₀ aryl-(CH₂)₁₋₆ --;

m is 0, 1, or 2;

R⁶ is hydrogen or C₁ -C₆ alkyl;

R⁷ is hydrogen or C₁ -C₆ alkyl;

R⁸ and R⁹ are selected independently from hydrogen, C₁ -C₆ alkyl,fluorine, chlorine, bromine, or iodine;

Y is S;

Z is N or CH;

or a pharmaceutically acceptable salt thereof.

The term C₁ -C₆ alkyl means a alkyl group consisting of from one to sixcarbon atoms which may be a straight or branched chain. The term C₁ -C₆alkoxy means an O--C₁ -C₆ alkyl group where the C₁ -C₆ group is asdefined above. The term C₆ -C₁₀ aryl means phenyl, 1-naphthyl or2-naphthyl and may be optionally substituted by one to threesubstituents as listed above according to commercial availability orsynthetic means. The term trifluoroalkyl means a group having theformula CF₃ --(CH₂)₀₋₂ -- and the term trifluoroalkoxy is anO-trifluoroalkyl group where trifluoroalkyl is as defined above.

Compounds of Formula I may be transformed into or isolated aspharmaceutically acceptable salts of alkali metals or alkaline earthmetals, such as a sodium, potassium, lithium or calcium salt. It willalso be recognized by those skilled in the art that the active compoundor salt thereof may be isolated as a solvate or hydrate which isconsidered to have the pharmacological properties of the activecompound.

The preferred compounds are those of Formula Ia below ##STR11## where:R¹⁰ is hydrogen, C₁ -C₆ alkyl, fluorine, chlorine, bromine, iodine, C₁-C₆ alkoxy, trifluoroalkyl or trifluoroalkoxy;

n is 1 or 2;

A is ##STR12## B is ##STR13## where m is 0, 1 or 2; R⁴, R⁵, R⁶, and R⁷are independently hydrogen or C₁ -C₆ alkyl;

Y is S;

Z is N or CH;

or a pharmaceutically acceptable salt thereof.

The most preferred compounds of this invention are those of Formula Ib##STR14## wherein: R¹⁰ is hydrogen, CF₃ --, CF₃ O--, CF₃ CH₂ O-- orCl--;

n is 1 or 2;

A is ##STR15## B is ##STR16## wherein m is 0 or 1; R⁴, R⁵, R⁶, and R⁷are independently hydrogen, methyl or ethyl;

Y is S;

Z is N or CH;

or a pharmaceutically acceptable salt thereof.

The most preferred compounds of the invention are the following:

(E)-2-(3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-pent-2-enyl)-[1,2,4]oxadiazolidine-3,5-dione,

(Z)-2-(3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-pent-2-enyl)-[1,2,4]oxadiazolidine-3,5-dione,

2-(3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-phenyl}-but-2-enyl)-[1,2,4]oxadiazolidine-3,5-dione,

(E)-2-(3-{3-[5-methyl-2-(4-trifluoromethoxy-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enyl)-[1,2,4]oxadiazolidine-3,5-dione,

(E)-2-(3-{3-[5-methyl-2-(4-trifluoro-ethoxy-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enyl)-[1,2,4]oxadiazolidine-3,5-dione,

(E)-2-{3-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-but-2-enyl}-[1,2,4]oxadiazolidine-3,5-dione,

(Z)-2-{3-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy]-phenyl]-but-2-enyl}-[1,2,4]oxadiazolidine-3,5-dione,

(E)-2-{3-[3-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-but-2-enyl)-[1,2,4]oxadiazolidine-3,5-dione,

2-{3-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy]-benzofuran-5-yl]-but-2-enyl}-[1,2,4]oxadiazolidine-3,5-dione,

(E)-2-(2-methyl-3-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-allyl)-[1,2,4]oxadiazolidine-3,5-dione,

(E)-2-(2-ethyl-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-allyl)-[1,2,4]oxadiazolidine-3,5-dione,

(E)-2-(1-methyl-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-allyl)-[1,2,4]oxadiazolidine-3,5-dione,

(E)-2-(3-{3-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-1-methyl-allyl)-[1,2,4]oxadiazolidine-3,5-dione,

(E)-2-(2-methyl-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enyl)-[1,2,4]oxadiazolidine-3,5-dione,

(Z)-2-(2-methyl-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enyl)-[1,2,4]oxadiazolidine-3,5-dione,

(E)-2-(1-methyl-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enyl)-[1,2,4]oxadiazolidine-3,5-dione,

2-[3-(4-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-allyl)-[1,2,4]oxadiazolidine-3,5-dione,

(E)-2-(2-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-cyclopropylmethyl)-[1,2,4]oxadiazolidine-3,5-dione,

(E)-2-(2-methyl-2-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-cyclopropylmethyl)-[1,2,4]oxadiazolidine-3,5-dione,

(E,E)-2-{5-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy]-phenyl}-hexa-2,4-dienyl)-[1,2,4]oxadiazolidine-3,5-dione,

(Z,E)-2-{5-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy]-phenyl}-hexa-2,4-dienyl)-[1,2,4]oxadiazolidine-3,5-dione,

2-[3-(4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl-oxazol-4-yl]-ethoxy}-phenyl)-propyl-2-ynyl)-[1,2,4]oxadiazolidine-3,5-dione,

2-{1-methyl-3-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propyl-2-ynyl}-[1,2,4]oxadiazolidine-3,5-dione,

(E)-5-{3-[3-(5-methyl-2-phenyl-oxazol-4-ylmethyl]-phenyl]-but-2-enyl}-oxazolidine-2,4-dione,

(E)-5-[3-(3-{5-methyl-2-[4-(2,2,2,-trifluoro-ethoxy)-phenyl]-oxazol-4-ylmethoxy}-phenyl)-but-2-enyl]-oxazolidine-2,4-dione,

(E)-5-(3-{3-[5-methyl-2-(trifluoromethoxy-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enyl)-oxazolidine-2,4-dione,

(E)-5-(3-{3-[2-(5-methyl-2-phenyl)-oxazol-4-yl)-ethoxy]-phenyl}-but-2-enyl)-oxazolidine-2,4-dione,(E)-5-{3-[3-(5-methyl-2-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enyl)-thiazolidine-2,4-dione,

(E)-5-(3-{3-[5-methyl-2-(4-trifluoromethoxy-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enyl)-thiazolidine-2,4-dione,and

(E)-2-(3-{3-[5-methyl-2-(4-trifluoromethoxy-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enyl)-[1,2,4]thiadiazolidine-3,5-dione.

DETAILED DESCRIPTION OF THE INVENTION

The invention compounds of Formula I may be prepared from intermediatesof the formula II below wherein the variables n, R¹, R², X, A and B areas previously defined. ##STR17## Oxadiazolidinediones of Formula I areprepared from a Formula II intermediate by first convening to ahydroxylamine followed by reaction with N-(chlorocarbonyl)isocyanate orby converting the Formula II alcohol to a N-hydroxyurea which is reactedwith methyl chloroformate to give a Formula I oxadiazolidinedione. TheFormula I oxazolidinediones and thiazolidinediones are prepared byconverting the intermediate of Formula II to the halide of Formula IIIbelow followed by reaction with 2,4-oxazolidinedione or2,4-thiazolidinedione. ##STR18## These synthetic transformations aremore fully described in the following reaction schemes I-XII.

Scheme I outlines the synthesis of a Formula II intermediate where A isphenyl and B is an olefinic linking group as shown under Formula I.##STR19## The terms R¹ -R⁵, X, n, and m are as defined previously.

Scheme II illustrates the synthetic sequence for preparing a Formula Icompound from the intermediate VIII. ##STR20## The terms R¹ -R⁵, X, n,and m are as defined previously.

When R⁴ is halogen the compounds of the present invention can beprepared according to Scheme III. ##STR21## wherein R¹, R², R³, X, and nare as defined above; R⁴ is halogen.

When R⁶ is alkyl the compounds of the present invention can be preparedaccording to Scheme IV ##STR22## wherein R¹, R², R³, R⁴, R⁵, R⁶, X, nand m are as defined above.

Scheme V outlines the synthesis of an intermediate where B iscyclopropylmethyl from an intermediate of Formula VIII where m is 0.##STR23## wherein R¹, R², R³, X, and n are as defined above; R⁴ ishydrogen, alkyl, aryl, aralkyl, cycloalkyl.

Scheme VI outlines the synthesis of a Formula II intermediate where B ispropynyl. ##STR24## wherein R¹, R², R³, R⁶, X, and n are as definedabove.

Scheme VII outlines the reactions used to prepare Formula I compoundswhere Z is CH and Y is O or S from an intermediate of Formula VIII.##STR25## wherein R¹, R², R³, R⁵, R⁶, X, n and m are as defined above;R⁴ is hydrogen, alkyl, allyl, aryl, aralkyl, trimethylsilyl, cycloalkyl;Y is O or S.

The Formula I thiadiazolidindiones where Y is S and Z is N are preparedas outlined in Scheme VIIa. ##STR26##

Preparation of a Formula I compound where A is benzofuran-2,5-diyl, Y isO and Z is N is shown in Scheme VIII. ##STR27## wherein R¹, R², R⁵, xand m are as defined above; R⁴ is hydrogen, alkyl, allyl, aryl, aralkyl,trimethylsilyl, cycloalkyl.

The starting heterocyclic intermediates of the formula V can be preparedaccording to standard literature procedures. For example,4-(1'-hydroxyethyl)-5-R² -2-phenyloxazoles and thiazoles where R² ishydrogen or C₁ -C₆ alkyl can be prepared according to Scheme IX(European Patent EP 0177353A2). ##STR28##

The starting heterocyclic intermediates of the formula IV can beprepared by known methods conventional in the art (HeterocyclicCompounds 34, 1979 and Heterocyclic Compounds 45, 1986). The2-phenyl-4-chloromethyl-5-methyloxazoles can be prepared according tothe reaction sequence shown in Scheme X. ##STR29##

The intermediate 4-chloromethyl-2-phenyloxazoles or thiazoles can beprepared according to the reaction shown in Scheme XI. ##STR30##

Intermediate of the formula VII can be prepared either from thecommercially available phenols of formula IX or according to thesynthetic Scheme XII. ##STR31## The formula I thiadiazolidines areprepared according to the following representative scheme.

The following examples are included for illustrative purposes and arenot intended to limit the disclosure of this invention in any way. Thereagents, intermediates, or chemicals used herein are eithercommercially available or can be readily synthesized using standardlaboratory procedures known to those skilled in the art.

Example 1(E)-2-(3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-pent-2-enyl)-[1,2,4]oxadiazolidine-3,5-dione

Step a)3-[5-methyl-2-(-4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy)-benzaldehyde

A mixture of4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole (5.25 g,19.1 mmol), 3-hydroxylbenzaldehyde (2.33 g, 19.1 mmol), potassiumcarbonate (3.77 g, 27.3 mmol) and dimethylformamide (50 mL) was stirredat 80° C. for 3 hours. The mixture was then poured into H₂ O, acidifiedwith HCl (2N) and extracted with EtOAc. The organic extracts were driedover MgSO₄. Evaporation and crystallization from ethyl ether/hexane,gave a yellow solid (4.47 g, 65% yield, m.p. 104°-105° C.).

Analysis for: C₁₉ H₁₄ F₃ NO₃ Calc'd: C, 63.16; H, 3.91; N, 3.88 Found:C, 62.84; H, 3.97; N, 3.87

Step b)l-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propan-1-one

Ethylmagnesium bromide (11.1 mL, 33.24 mmol) was added dropwise in to acold (0° C.) solution of3-[5-methyl-2-(-4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy)-benzaldehyde(12.0 g, 33.24 mmol) and THF (50 mL). After stirring for 30 minutes thereaction mixture was quenched with aqueous NH₄ Cl, poured into water,acidified with HCl (2N) and extracted with EtOAc. The organic extractswere dried over MgSO₄. Evaporation gave a yellowish oil (13.0 g), whichwas dissolved in acetone (200 mL). The mixture was cooled to 5° C. andfreshly prepared Jones' Reagent (40 mL) was added dropwise. After theaddition, the mixture was stirred for 30 minutes, poured into water andextracted with EtOAc. The organic extracts were dried over MgSO₄.Evaporation and crystallization from ethyl ether/hexane (after coolingto 0° C.), gave a white solid (9.6 g, 74% yield, m.p. 73°-74° C.).

Analysis for: C₃₈ H₃₆ N₂ O₉ Calc'd: C, 64.78; H, 4.66; N, 3.60 Found: C,64.63; H, 4.60; N, 3.91

Step c)(E)-3-{3-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-pent-2-enoicacid ethyl ester

Triethylphosphonoacetate (8.67 ml, 43.1 mmol) was added dropwise in to acold (0° C.) suspension of sodium hydride (1.24 g, 41.5 mmol) andtoluene (200 ml). After the addition, the mixture was stirred for 1hour, and then1-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propan-1-one(8.5 g, 21.85 mmol) in THF (20 ml) was added dropwise. The reactionmixture was stirred at room temperature for 24 hours, poured into water,acidified with HCl (2N), and extracted with EtOAc. The organic extractswere dried over MgSO₄. Evaporation and purification by flashchromatography on silica gel (hexane/EtOAc 8/1) gave the trans-isomer(white solid, 5.5 g, 55% yield, m.p. 85°-86° C.), and the cis-isomer(clear oil, 2.8 g 28% yield).

a) Analysis for: C₂₅ H₂₄ F₃ NO₄ (trans-isomer) Calc'd: C, 65.35; H,5.27; N, 3.05 Found: C, 65.25; H, 5.42; N, 3.01

b) Analysis for: C₂₅ H₂₄ F₃ NO₄ (cis-isomer) Calc'd: C, 65.35; H, 5.27;N, 3.05 Found: C, 65.11; H, 5.31; N, 3.00

Step d)(E)-3-{3-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-pent-2-en-1-ol

Di-isobutyl aluminum hydride (1.0M in THF, 25.05 ml, 25.05 mmol) wasadded dropwise in to a cold (-50° C.) solution of(E)-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-pent-2-enoicacid ethyl ester (4.6 g, 10 mmol) in THF (100 ml) and ethyl ether (100mL). The reaction was warmed to 0° C. and stirred for 1 hour. Thereaction mixture was quenched with acetone (dropwise addition),methanol, poured into water, acidified with HCl (2N), and extracted withEtOAc. The organic extracts were dried over MgSO₄. Evaporation andpurification by flash chromatography on silica gel (hexane/EtOAc 3/1),gave a clear oil (3.8 g, 91% yield).

Analysis for: C₂₃ H₂₂ F₃ NO₃ Calc'd: C, 66.18; H, 5.31; N, 3.36 Found:C, 65.88; H, 5.41; N, 3.26

Step e)(E)-N-tert-Butoxycarbonyloxy-(3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-pent-2-enyl)-carbamicacid tert-butyl ester

Diisopropylazodicarboxylate (1.98 ml, 10.07 mmol) in THF (15 ml) wasadded dropwise n to a cold (-20° C.) solution of(E)-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-pent-2-en-1-ol(3.5 g, 8.39 mmol) in THF (30 ml), triphenylphosphine (2.64 g, 10.07mmol) and tert-butyl N-(tert-butoxy-carbonyloxy) carbamate (2.35 g,10.07 mmol). After the addition, the mixture was stirred for 1 hour,poured into water, and extracted with EtOAc. The organic extracts weredried over MgSO₄. Evaporation and purification by flash chromatographyon silica gel (hexane/EtOAc 7/1) gave a clear oil (5.1 g, 96% yield).

Analysis for: C₃₃ H₃₉ F₃ N₂ O₇ ×0.5 H₂ O Calc'd: C, 61.77; H, 6.24; N,4.37 Found: C, 61.58; H, 6.46; N, 4.60

Step f)(E)-N-(3-{3-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-pent-2-enyl)-hydroxylamine

A mixture of(E)-N-tert-butoxycarbonyloxy-3-(3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-pentyl-2-enyl)-carbamicacid tert-butyl ester (5.0 g, 7.9 mmol), CH₂ Cl₂ (100 ml), andtrifluoroacetic acid (10 ml) was stirred at room temperature for 8 h.The volatiles were removed in vacuo, and the residue taken inethylether/water. It was basified to pH=9-10 with NaOH (2N), and theorganic layer separated and washed with water and brine. The organicextracts were dried over MgSO₄. Evaporation and purification by flashchromatography on silica gel (hexane/EtOAc 1/1, and MeOH/EtOAc 1/10),gave a clear oil (3.0 g, 88% yield).

Analysis for: C₂₃ H₂₃ F₃ N₂ O₃ Calc'd: C, 63.88; H, 5.36; N, 6.48 Found:C, 63.63; H, 5.27; N, 6.48

Step g)(E)-2-(3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-pent-2-enyl)-[1,2,4]oxadiazolidine-3,5-dione

N-(Chlorocarbonyl)isocyanate (0.37 ml, 4.63 mmol) was added dropwise toa cold (-5° C.) mixture of(E)-N-(3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-pent-2-enyl)-hydroxylamine(2.0 g, 4.63 mmol) in THF (20 ml). The mixture was stirred for 30minutes, then poured into HCl (1N) and extracted with EtOAc. The organicextracts were dried over MgSO₄. Evaporation and purification by flashchromatography on acid washed (5% H₃ PO₄ /MeOH) silica gel (hexane/EtOAc3/1) gave a white solid (1.48 g, 64% yield, mp 66°-67° C.).

Analysis for: C₂₅ H₂₂ F₃ N₃ O₅ Calc'd: C, 59.88; H, 4.42; N, 8.38 Found:C, 59.83; H, 4.37; N, 8.28

Example 2(E)-2-(3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-pent-2-enyl)-[1,2,4]oxadiazolidine-3,5-dione

Step a)(Z)-3-{3-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-pent-2-en-1-ol

Di-isobutyl aluminum hydride (1.0M in THF, 10.89 ml, 10.89 mmol) wasadded dropwise in to a cold (-50° C.) solution of(Z)-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-pent-2-enoicacid ethyl ester (2.0 g, 4.35 mmol) in THF (30 ml) and ethyl ether (30mL). The reaction was warmed to 0° C. and stirred for 1 hour. Thereaction mixture was quenched with acetone (dropwise addition),methanol, poured into water, acidified with HCl (2N), and extracted withEtOAc. The organic extracts were dried over MgSO₄. Evaporation andpurification by flash chromatography on silica gel (hexane/EtOAc 3/1),gave a white solid (1.65 g, 91% yield, m.p. 88°-89° C.).

Analysis for: C₂₃ H₂₂ F₃ NO₃ Calc'd: C, 66.18; H, 5.31; N, 3.36 Found:C, 65.85; H, 5.12; N, 3.15

Step b)(Z)-N-(3-{3-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-pent-2-enyl)-hydroxylamine

Diisopropylazodicarboxylate (0.68 ml, 3.45 mmol) in THF (10 ml) wasadded dropwise n to a cold (-20° C.) solution of(Z)-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-pent-2-en-1-ol(1.2 g, 2.87 mmol), THF (20 ml), triphenylphosphine (0.9 g, 3.45 mmol)and tert-butyl N-(tert-butoxy-carbonyloxy) carbamate (0.8 g, 3.45 mmol).After the addition, the mixture was stirred for 1 hour, poured intowater, and extracted with EtOAc. Evaporation gave a yellowish oil (1.7g), which was dissolved in CH₂ Cl₂ (30 mL), and treated withtrifluoroacetic acid (3.0 mL). After stirring at room temperature for 8hours, the volatiles were removed in vacuo, and the residue taken inethylether/water. It was basified to pH=9-10 with NaOH (2N), and theorganic layer separated and washed with water and brine. The organicextracts were dried over MgSO₄. Evaporation and purification by flashchromatography on silica gel (hexane/EtOAc 1/1, and MeOH/EtOAc 1/10),gave a white solid (3.0 g, 82% yield, m.p. 72°-73° C.).

Analysis for: C₂₃ H₂₃ F₃ N₂ O₃ Calc'd: C, 63.88; H, 5.36; N, 6.48 Found:C, 63.74; H, 5.34; N, 6.26

Step c)(Z)-2-(3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-pent-2-enyl)-[1,2,4]oxadiazolidine-3,5-dione

N-(Chlorocarbonyl)isocyanate (0.12 ml, 1.5 mmol) was added dropwise to acold (-5° C.) mixture of(Z)-N-(3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-pent-2-enyl)-hydroxylamine(0.65 g, 1.5 mmol) in THF (10 ml). The mixture was stirred for 30minutes, then poured into HCl (1N) and extracted with EtOAc. The organicextracts were dried over MgSO₄. Evaporation and purification by flashchromatography on acid washed (5% H₃ PO₄ /MeOH) silica gel (hexane/EtOAc2/1) gave a white solid (0.48 g, 64% yield, mp 126°-127° C.).

Analysis for: C₂₅ H₂₂ F₃ N₃ O₅ Calc'd: C, 59.88; H, 4.42; N, 8.38 Found:C, 60.03; H, 4.55; N, 8.03

Example 3(E)-2-(3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-phenyl}-but-2-enyl)-[1,2,4]oxadiazolidine-3,5-dione

Step a) 4,5-Dimethyl-2-(4-trifluoromethyl-phenyl)-oxazole N-oxidehydrochloride

HCl gas (21.2 g, 58.1 mmol) was bubbled via syringe into a 0° C.solution of 4-trifluoromethylbenzaldehyde (50 g, 28.7 mmol),2,3-butanedione monoxime (26.40 g, 26.1 mmol), and EtOAc (105 ml). Thereaction was stirred at 5° C. for 3 h. Ice cold ether (575 ml) was thenadded, and the resultant precipitate was filtered, washed with ether,and dried at 25° C. for 16 h to give the product as a white solid (54.79g, 71% yield, mp 149°-159° C.).

Analysis for: C₁₂ H₁₁ ClF₃ NO₂ Calc'd: C, 49.08; H, 3.77; N, 4.77 Found:C, 49.48; H, 3.81; N, 4.88

Step b) 4-Chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole

In to a 5° C. solution of4,5-dimethyl-2-(4-trifluoromethyl-phenyl)-oxazole N-oxide hydrochloride(113.71 g, 387.5 mmol) in CHCl₃ (560 ml), was added phosphorusoxychloride (39.4 ml, 422.4 mmol) in CHCl₃, dropwise over 15 min. Thereaction was refluxed for 2.5 h, then cooled to 5° C., poured into icewater, and basified with NaOH (1N). The organic layer was dried overMgSO₄. Evaporation and recrystallization from ether/hexane, gave ayellow solid (30.0 g, 28% yield, mp 84°-85° C.).

Analysis for: C₁₂ H₉ ClF₃ NO Calc'd: C, 52.29; H, 3.29; N, 5.08 Found:C, 52.54; H, 3.20; N, 4.92

Step c)1-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-ethanone

A mixture of4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole (24.3 g,88.2 mmol), 3-hydroxyacetophenone (10.0 g, 73.5 mmol), and potassiumcarbonate (13.2 g, 95.6 mmol), was stirred at 70° C. for 16 h. Thereaction was poured into water, acidified with HCl (1N), and extractedwith EtOAc. The organic extracts were dried over MgSO₄. Evaporation andpurification by flash chromatography on silica gel (hexane/EtOAc 9/1),gave an off-white solid (20.14 g, 60% yield, mp 90°-91° C.).

Analysis for: C₂₀ H₁₆ F₃ NO₃ Calc'd: C, 63.99; H, 4.29; N, 3.73 Found:C, 63.86; H, 4.30; N, 3.64

Step d)(E)-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enoicacid ethyl ester

In to a 0° C. mixture of sodium hydride (4.27 g, 142.6 mmol) and toluene(500 ml), was added triethylphosphonoacetate (29.79 ml, 150.1 mmol) viasyringe. The reaction was stirred for 1 hour, and then1-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-ethanone(28.15 g, 75.1 mmol) in THF (150 ml) was added dropwise. The reactionmixture was stirred at room temperature for 16 h, poured into water,acidified with HCl (2N), and extracted with EtOAc. The organic extractswere dried over MgSO₄. Evaporation and purification by flashchromatography on silica gel (hexane/EtOAc 20/1) gave a white solid(24.42 g, 73% yield, mp 91°-92° C.).

Analysis for: C₂₄ H₂₃ F₃ NO₄ Calc'd: C, 64.57; H, 5.19; N, 3.14 Found:C, 64.81; H, 5.01; N, 3.13

Step e)(E)-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-en-1-ol

Di-isobutyl aluminum hydride (1.0M in THF) (219.2 ml, 219.2 mmol) wasadded, by syringe, to a -25° C. solution of3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enoicacid ethyl ester (24.42 g, 54.8 mmol) in THF (300 ml). The reaction waswarmed to 0° C. and stirred for 1.5 h. It was poured into ice water,acidified with HCl (2N), stirred for 45 min, then extracted with EtOAc.The organic extracts were dried over MgSO₄. Evaporation and purificationby flash chromatography on silica gel (hexane/EtOAc 3/1), gave a lightyellow solid (17.68 g, 82% yield, mp 145°-146° C.).

Analysis for: C₂₂ H₁₈ F₃ NO₃ Calc'd: C, 65.83; H, 4.52; N, 3.49 Found:C, 65.78; H, 4.53; N, 3.45

Step f)(E)-N-tert-Butoxycarbonyloxy-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enyl)-carbamicacid tert-butyl ester

In to a -20° C. solution of3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-en-1-ol(3.1 g, 7.69 mmol) in THF (50 ml), was added triphenylphosphine (2.42 g,9.23 mmol) and tert-butyl N-(tert-butoxy-carbonyloxy) carbamate (2.15 g,9.23 mmol). Diethylazodicarboxylate (1.45 ml, 9.23 mmol) in THF (10 ml)was then added via syringe, and the reaction was stirred for 1 h at 0°C. The reaction was poured into water, and extracted with EtOAc. Theorganic extracts were dried over MgSO₄. Evaporation and purification byflash chromatography on silica gel (hexane/EtOAc 6/1) gave a lightyellow oil (4.69 g, 98% yield).

Analysis for: C₃₂ H₃₇ F₃ N₂ O₇ Calc'd: C, 62.13; H, 6.03; N, 4.53 Found:C, 62.17; H, 6.12; N, 4.67

Step g)(E)-N-(3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]phenyl}-but-2-enyl)-hydroxylamine

Trifluoroacetic acid (20 ml) was added in to a solution of(E)-N-tert-butoxycarbonyloxy-3-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enyl)-carbamicacid tert-butyl ester (4.5 g, 7.28 mmol) and CH₂ Cl₂ (40 ml). Thereaction mixture was stirred at room temperature for 8 h. The volatileswere removed in vacuo, and the residue taken in ether/water. It wasbasified to pH=9-10 with NaOH (2N), and the organic layer separated andwashed with water and brine. The organic layer was dried over MgSO₄.Evaporation and purification by flash chromatography on silica gel(hexane/EtOAc 1/1 and MeOH/EtOAc 1/10), gave a clear oil (2.70 g, 88%yield).

Analysis for: C₂₂ H₂₁ F₃ N₂ O₃ Calc'd: C, 63.15; H, 5.06; N, 6.70 Found:C, 63.34; H, 4.79; N, 6.53

Step h)(E)-2-(3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-phenyl}-but-2-enyl)-[1,2,4]oxadiazolidine-3,5-dione

N-(Chlorocarbonyl)isocyanate (0.548 ml, 6.22 mmol) was added dropwise toa -5° C. mixture ofN-(3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enyl)-hydroxylamine(2.6 g, 6.22 mmol) in THF (25 ml). The mixture was stirred for 30 min,then poured into HCl (1N) and extracted with EtOAc. The organic extractswere dried over MgSO₄. Evaporation and purification by flashchromatography on acid washed (5% H₃ PO₄ /MeOH) silica gel (hexane/EtOAc3/1), gave a white solid (1.85 g, 61% yield, mp 136°-138° C.).

Analysis for: C₂₄ H₂₀ F₃ N₃ O₅ Calc'd: C, 59.14; H, 4.13; N, 8.62 Found:C, 58.95; H, 3.92; N, 8.77

Example 4(E)-2-(3-{3-[5-methyl-2-(4-trifluoromethoxy-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enyl)-[1,2,4]oxadiazolidine-3,5-dione

The title compound was prepared in substantially the same manner asdescribed in Example 3, and was obtained as a white solid, mp 145°-146°C.

Analysis for: C₂₄ H₂₀ F₃ N₃ O₆ Calc'd: C, 57.26; H, 4.00; N, 8.35 Found:C, 57.26; H, 3.94; N, 8.22

Example 5(E)-2-[3-(3-{5-methyl-2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-oxazol-4-ylmethoxy}-phenyl)-but-2-enyl]-[1,2,4]oxadiazolidine-3,5-dione

The title compound was prepared in substantially the same manner asdescribed in Example 3, and was obtained as a white solid, mp 145°-146°C.

Analysis for: C₂₅ H₂₂ F₃ N₃ O₆ Calc'd: C, 58.03; H, 4.29; N, 8.12 Found:C, 58.05; H, 3.28; N, 8.30

Example 6(E)-2-{3-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-but-2-enyl}-[1,2,4]oxadiazolidine-3,5-dione

The title compound was prepared in substantially the same manner asdescribed in Example 3, and was obtained as a white solid, mp 131°-132°C.

Analysis for: C₂₃ H₂₁ N₃ O₅ Calc'd: C, 65.86; H, 5.05; N, 10.02 Found:C, 65.89; H, 5.10; N, 9.87

Example 7(Z)-2-{3-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy]-phenyl]-but-2-enyl}-[1,2,4]oxadiazolidine-3,5-dione

The title compound was prepared in substantially the same manner asdescribed in Example 3, and was obtained as a white solid, mp 118°-119°C.

Analysis for: C₂₃ H₂₁ N₃ O₅ Calc'd: C, 65.86; H, 5.05; N, 10.02 Found:C, 65.83; H, 5.18; N, 9.97

Example 8(E)-2-(3-{3-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-but-2-enyl)-[1,2,4]oxadiazolidine-3,5-dione

The title compound was prepared in substantially the same manner asdescribed in Example 2. The required1-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-ethanone wasprepared according to the following procedure. The title compound wasobtained as a white solid, m.p. 142°-143° C.

Analysis for: C₂₄ H₂₃ N₃ O₅ Calc'd: C, 66.50; H, 5.35; N, 9.69 Found: C,66.18; H, 5.41; N, 9.48

Preparation of1-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-ethanone

Diethylazodicarboxylate (20.7 mL, 131.6 mmol) in THF (35 mL) was addeddropwise in to a cold (0° C.) solution of4-(2'-hydroxy-ethyl)-5-methyl-2-phenyloxazole (25.0 g, 123.0 mmol),triphenylphosphine (34.5 g, 131.6 mmol), and 3'-hydroxyacetophenone(18.0 g, 131.6 mmol) and THF (180 mL). The mixture was allowed to cometo room temperature and stirred for 48 hours. Then, it was poured intoH₂ O, acidified with HCl (2N) and extracted with EtOAc. The organicextracts were dried over MgSO₄. Evaporation and purification by flashchromatography on silica gel (hexane/EtOAc 5/1) gave a white solid (30.5g, 77% yield, m.p. 70°-71° C.).

Analysis for: C₂₀ H₁₉ NO₃ Calc'd: C, 74.75; H, 5.96; N, 4.36 Found: C,74.70; H, 6.15; N, 4.28

Example 9(E)-2-{3-[2-(5-methyl-2-phenyl-oxazol-4-ylmethyl]-benzofuran-5-yl]-but-2-enyl}-[1,2,4]oxadiazolidine-3,5-dione

Step a)1-[2-(5-methyl-2-phenyl-oxazol-4-ylmethyl)-benzofuran-5-yl]-ethanol

Methyl magnesium choride (4.2 ml, 12.62 mmol) was added in to a cold (0°C.) solution of2-(5-methyl-2-phenyl-oxazol-4-ylmethyl)-benzofuran-5-carbaldehyde(prepared according to EP 0 428 312 A2, 4.0 g, 12.62 mmol) and THF (20ml). The reaction was stirred at 0° C. for 20 min, and at roomtemperature for 30 min, then poured into water, acidified with HCl (2N)and extracted with EtOAc. The organic extracts were dried over MgSO₄.Evaporation and purification by flash chromatography on silica gel(hexane/EtOAc 2/1) gave a yellow solid (3.75 g, 88% yield, mp 103°-105°C.).

Analysis for: C₂₁ H₁₉ NO₃ Calc'd: C, 75.66; H, 5.74; N, 4.20 Found: C,75.35; H, 5.80; N, 4.11

Step b)1-[2-(5-methyl-2-phenyl-oxazol-4-ylmethyl)-benzofuran-5-yl]-ethanone

Freshly prepared Jones' Reagent (6.5 mL, 10.51 mmol) was added dropwisein to a cold (10° C.) solution of1-[2-(5-methyl-2-phenyl-oxazol-4-ylmethyl)-benzofuran-5-yl]-ethanol (3.5g, 10.51 mmol) and acetone (50 mL). After 30 min, the mixture was pouredinto water, and extracted with ethyl ether/EtOAc: 1/1. The organicextracts were dried over MgSO₄. Evaporation and purification by flashchromatography on silica gel (hexane/EtOAc 2/1), gave a yellow solid(3.4 g, 97% yield, mp 108°-109° C.).

Analysis for: C₂₁ H₁₇ NO₃ Calc'd: C, 76.12; H, 5.17; N, 4.23 Found: C,76.38; H, 5.13; N, 4.09

Step c)(E)-3-[2-(5-methyl-2-phenyl-oxazol-4-ylmethyl)-benzofuran-5-yl]-but-2-enoicacid ethyl ester

The title compound was prepared in substantially the same manner asdescribed in Example 3, step d, and was obtained as a white solid, m.p.81°-83° C.

Analysis for: C₂₅ H₂₃ NO₄ Calc'd: C, 74.80; H, 5.77; N, 3.49 Found: C,74.68; H, 5.75; N, 3.40

Step d)(E)-3-[2-(5-methyl-2-phenyl-oxazol-4-ylmethyl)-benzofuran-5-yl]-but-2-en-1-ol

The title compound was prepared in substantially the same manner asdescribed in Example 3, step e, and was obtained as a white solid, m.p.119°-121° C.

Analysis for: C₂₃ H₂₁ NO₃ Calc'd: C, 76.86; H, 5.89; N, 3.90 Found: C,76.71; H, 5.87; N, 3.77

Step e)(E)-1-hydroxy-1-(3-[2-(5-methyl-2-phenyl-oxazol-4-ylmethyl)-benzofuran-5-yl]-but-2-enyl)-urea

Diethylazodicarboxylate (2.56 mL, 16.3 mmol) was added dropwise in to acold (-20° C.) mixture of(E)-3-[2-(5-methyl-2-phenyl-oxazol-4-ylmethyl)-benzofuran-5-yl]-but-2-en-1-ol(4.5 g, 12.5 mmol), triphenylphosphine (4.27 g, 16.3 mmol),N,O-bis(carbophenoxy)hydroxylamine (4.45 g, 16.3 mmol) and THF (100 mL).After stirring for 30 minutes at -20° C., the mixture was allowed tocome to 0° C. and stirred for 2 hours. Then, it was poured into H₂ O andextracted with EtOAc. The organic extracts were dried over MgSO₄.Evaporation gave a yellow oil (6.5), which was placed in a pressurevessel. Anhydrous ammonia (20 mL) was condensed in the vessel. Themixture was stirred at -5° C. to -10° C. for 3 hours and then at roomtemperature 18 hours. The excess ammonia was allowed to escape in to anacidic solution and the residue was recrystallized from ethylether/acetone, to give a white solid (2.5 g, 48% yield, m.p. 111°-113°C.).

Analysis for: C₂₄ H₂₃ N₃ O₄ Calc'd: C, 69.05; H, 5.55; N, 10.07 Found:C, 68.66; H, 5.36; N, 9.83

Step f)(E)-1-Methoxycarbonyloxy-1-(3-[2-(5-methyl-2-phenyl-oxazol-4-ylmethyl)-benzofuran-5-yl]-but-2-enyl)-urea

Sodium hydride (0.3 g, 10.0 mmol) was added portionwise in to a cold(0°) solution of(E)-1-hydroxy-1-(3-[2-(5-methyl-2-phenyl-oxazol-4-ylmethyl)-benzofuran-5-yl]-but-2-enyl)-urea(1.9 g, 4.55 mmol) and THF (20 mL). After stirring for 1 hour, methylchloroformate (1.6 mL, 18.2 mmol) was added dropwise. The reactionmixture was stirred for 1 hour, poured in to dioxane (50 mL)/MaOH (2N, 5mL) solution and after 10 minutes acidified with HCl (2N) and extractedwith EtOAc. The organic extracts were dried over MgSO₄. Evaporation andpurification by flash chromatography on silica gel (hexane/EtOAc 2/1),gave a yellow solid (1.72 g, 79% yield, m.p. 65°-67° C.).

Analysis for: C₂₆ H₂₅ N₃ O₆ Calc'd: C, 65.68; H, 5.30; N, 8.84 Found: C,65.94; H, 5.06; N, 8.83

Step g)(E)-2-{3-[2-(5-methyl-2-phenyl-oxazol-4-ylmethyl]-benzofuran-5-yl]-but-2-enyl}-[1,2,4]oxadiazolidine-3,5-dione

Sodium hydride (76 mg, 2.52 mmol) was added portionwise in to a cold(0°) solution ofE)-N-carbamoyl-N-methoxycarbonyloxy-3-[2-(5-methyl-2-phenyl-oxazol-4-ylmethyl)-benzofuran-5-yl]-but-2-enyl-amine(1.2 g, 2.52 mmol) and DMF (10 mL). The reaction mixture was stirred for30 minutes and then poured into water (10 mL), acidified with HCl (2N)and extracted with EtOAc. The organic extracts were dried over MgSO₄.Evaporation and crystallization from ethyl ether, gave a yellow solid(0.72 g, 65% yield, m.p. 163°-165).

Analysis for: C₂₅ H₂₁ N₃ O₅ Calc'd: C, 67.71; H, 4.77; N, 9.47 Found: C,67.79; H, 4.56; N, 9.39

Example 10(E)-2-(2-methyl-3-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-allyl)-[1,2,4]oxadiazolidine-3,5-dione

Step a)(E)-2-methyl-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-acrylicacid ethyl ester

Triethyl 2-phosphonopropionate (2.64 ml, 11.08 mmol) was added dropwisein to a cold (0° C.) suspension of sodium hydride (0.31 g, 10.52 mmol)and toluene (50 ml). After the addition, the mixture was stirred for 1hour, and then3-[5-methyl-2-(-4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy)-benzaldehyde(2.0 g, 5.54 mmol) in THF (10 ml) was added dropwise. The reactionmixture was stirred at room temperature for 24 hours, poured into water,acidified with HCl (2N), and extracted with EtOAc. The organic extractswere dried over MgSO₄. Evaporation and purification by flashchromatography on silica gel (hexane/EtOAc 8/1) gave a clear oil (2.2 g,89% yield).

Analysis for: C₂₄ H₂₂ F₃ NO₄ Calc'd: C, 64.71; H, 4.98; N, 3.14 Found:C, 64.82; H, 4.99; N, 2.93

Step b)(E)-2-methyl-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-prop-2-en-1-ol

The title compound was prepared in substantially the same manner asdescribed in Example 3, step e, and was obtained as a white solid, m.p.90°-91° C.

Analysis for: C₂₂ H₂₀ F₃ NO₃ Calc'd: C, 65.50; H, 4.99; N, 3.47 Found:C, 65.40; H, 5.12; N, 3.33

Step c)(E)-2-methyl-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-allyl)-hydroxylamine

The title compound was prepared in substantially the same manner asdescribed in Example 2, step b, and was obtained as a yellow oil.

Analysis for: C₂₂ H₂₁ F₃ N₂ O₃ Calc'd: C, 63.15; H, 5.06; N, 6.69Found.: C, 62.82; H, 4.99; N, 6.64

Step d)(E)-2-(2-methyl-3-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-allyl)-[1,2,4]oxadiazolidine-3,5-dione

The title compound was prepared in substantially the same manner asdescribed in Example 1, step h, and was obtained as a white solid, mp144°-146° C.

Analysis for: C₂₄ H₂₀ F₃ N₃ O₅ Calc'd: C, 59.14; H, 4.13; N, 8.62 Found:C, 59.20; H, 3.95; N, 8.57

Example 11(E)-2-(2-ethyl-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-allyl)-[1,2,4]oxadiazolidine-3,5-dione

The title compound was prepared in substantially the same manner asdescribed in Example 10, and was obtained as a white solid, mp 124°-125°C.

Analysis for: C₂₅ H₂₂ F₃ N₃ O₅ Calc'd: C, 59.88; H, 4.42; N, 8.38 Found:C, 59.94; H, 4.40; N, 8.34

Example 122-(1-Methyl-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-allyl)-[1,2,4]oxadiazolidine-3,5-dione

Step a)3-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzaldehyde

The title compound was prepared in substantially the same manner asdescribed in example 1, step a, and was obtained as a yellow solid, mp104°-105° C.

Analysis for: C₁₉ H₁₄ F₃ NO₃ Calc'd: C, 63.16; H, 3.91; N, 3.88 Found:C, 62.84; H, 3.97; N, 3.87

Step b)(E)-4-{3-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-3-en-2-one

A solution of sodium hydroxide (1.13 g, 28.25 mmol) in water (15 mL),was added to a mixture of3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzaldehyde(6.0 g, 16.62 mmol) and acetone (100 mL). The reaction was stirred for 1hour, and the excess acetone was removed in vacuo. The residue wasacidified with HCl (1N), stirred for 10 min, then extracted with EtOAc.The organic extracts were dried over MgSO₄. Evaporation and purificationby flash chromatography on silica gel (EtOAc 4/1) gave a white solid(4.6 g, 69% yield, mp 84°-84° C.).

Analysis for: C₂₂ H₁₈ F₃ NO₃ Calc'd: C, 65.83; H, 4.52; N, 3.49 Found:C, 65.74; H, 4.41; N, 3.52

Step c)(E)-4-{3-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-3-en-2-ol

Sodium borohydride (0.389 g, 10.22 mmol) was added to a -20° C. solutionof(E)-4-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-3-en-2-one(4.1 g, 10.22 mmol), cerium trichloride (3.81 g, 10.22 mmol), methanol(150 mL), and THF (30 mL). The reaction was stirred for 30 min, thenpoured into water, acidified with HCl (2N), an extracted with EtOAc. Theorganic extracts were dried over MgSO₄. Evaporation and purification byflash chromatography on silica gel (hexane/EtOAc 2/1), gave a whitesolid (3.7 g, 89% yield, mp 48°-50° C.).

Analysis for: C₂₂ H₂₀ F₃ NO₃ Calc'd: C, 65.50; H, 4.99; N, 3.47 Found:C, 65.78; H, 5.07; N, 3.58

Step d)(E)-N-(1-Methyl-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-allyl)-hydroxylamine

The title compound was prepared in substantially the same manner asdescribed in Example 1, step b, and was obtained as a white solid, m.p.118°-120° C.

Analysis for: C₂₂ H₂₁ F₃ N₂ O₃ Calc'd: C, 63.15; H, 5.06; N, 6.69 Found:C, 62.72; H, 5.04; N, 6.59

Step e)2-(1-methyl-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-allyl)-[1,2,4]oxadiazolidine-3,5-dione

The title compound was prepared in substantially the same manner asdescribed in Example 2, step c, and was obtained as a white solid, mp119°-121° C.

Analysis for: C₂₄ H₂₀ F₃ N₃ O₅ Calc'd: C, 59.14; H, 4.13; N, 8.62 Found:C, 59.00; H, 3.96; N, 8.82

Example 13(E)-2-(3-{3-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-1-methyl-allyl)-[1,2,4]oxadiazolidine-3,5-dione

The title compound was prepared in substantially the same manner asdescribed in Example 12, and was obtained as a white solid, mp 172°-174°C.

Analysis for: C₂₃ H₂₀ ClN₃ O₅ Calc'd: C, 60.86; H, 4.44; N, 9.26 Found:C, 60.92; H, 4.39; N, 9.17

Example 14(E)-2-(2-methyl-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enyl)-[1,2,4]oxadiazolidine-3,5-dione

Step a)(E)-2-methyl-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enoicacid ethyl ester,

(Z)-2-methyl-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enoicacid ethyl ester

The title compounds was prepared in substantially the same manner asdescribed in Example 1, step c, and were obtained as white solids.

(trans-) Analysis for: C₂₅ H₂₄ F₃ NO₄ Calc'd: C, 65.35; H, 5.26; N,2.3.05 Found: C, 66.74; H, 5.39; N, 2.84

(cis-) Analysis for: C₂₅ H₂₄ F₃ NO₄ Calc'd: C, 65.45; H, 5.26; N, 3.05Found: C, 65.45; H, 5.29; N, 2.80

Step b)(E)-2-methyl-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-en-1-ol

The title compound was prepared in substantially the same manner asdescribed in Example 2, step a, and was obtained as a white solid, m.p.115°-116° C.

Analysis for: C₂₃ H₂₂ F₃ NO₃ Calc'd: C, 66.18; H, 5.31; N, 3.56 Found:C, 66.04; H, 5.32; N, 3.49

Step c)(E)-N-(2-Methyl-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enyl)-hydroxylamine

The title compound was prepared in substantially the same manner asdescribed in Example 2, step b, and was obtained as a white solid, m.p.115°-116° C.

Analysis for: C₂₃ H₂₃ F₃ N₂ O₃ ×1 H₂ O Calc'd: C, 61.33; H, 5.55; N,6.22 Found: C, 61.34; H, 5.57; N, 5.84

Step d)(E)-2-(2-methyl-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enyl)-[1,2,4]oxadiazolidine-3,5-dione

The title compound was prepared in substantially the same manner asdescribed in Example 2, step c, and was obtained as a white solid, m.p.152°-153° C.

Analysis for: C₂₅ H₂₂ F₃ N₃ O₅ Calc'd: C, 59.88; H, 4.42; N, 8.38 Found:C, 59.79; H, 4.33; N, 8.16

Example 15(Z)-2-(2-methyl-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enyl)-[1,2,4]oxadiazolidine-3,5-dione

The title compound was prepared in substantially the same manner asdescribed in Example 13, and was obtained as a white solid, m.p.144°-145° C.

Analysis for: C₂₅ H₂₂ F₃ N₃ O₅ Calc'd: C, 59.88; H, 4.42; N, 8.38 Found:C, 59.69; H, 4.45; N, 8.37

Example 16(E)-2-(1-methyl-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enyl}-[1,2,4]oxadiazolidine-3,5-dione

Step a)(E)-3-{3-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enal

In to a solution of(E)-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-en-1-ol(21.48 g, 53.3 mmol) in CH₂ Cl₂ (500 ml), was added manganese dioxide(27.8 g, 319.8 mmol), and the reaction was stirred at room temperaturefor 60 h. The mixture was filtered through solka floc. Evaporation andpurification by flash chromatography on silica gel (hexane/EtOAc 7/1),gave a light yellow solid (17.68 g, 82% yield, m.p. 145°-146° C.).

Analysis for: C₂₂ H₁₈ F₃ NO₃ Calc'd: C, 65.83; H, 4.52; N, 3.49 Found:C, 65.78; H, 4.53; N, 3.45

Step b)(E)-4-{3-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-pent-3-en-2-ol

Methyl magnesium bromide (3.0M in ether) (13.9 ml, 41.4 mmol) was addedto a 0° C. mixture of(E)-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enal(16.68 g, 41.6 mmol) in THF (200 ml). The reaction was stirred at 0°-5°C. for 25 min, then poured into water, acidified with HCl (2N), andextracted with EtOAc. The organic extracts were dried over MgSO₄.Evaporation and purification by flash chromatography on silica gel(hexane/EtOAc 4/1), gave a yellow solid (5.85 g, 33% yield, m.p. 45°-47°C.).

Analysis for: C₂₃ H₂₂ F₃ NO₃ Calc'd: C, 66.18; H, 5.31; N, 3.36 Found:C, 65.97; H, 5.24; N, 3.34

Step c)(E)-N-(1-Methyl-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2--enyl)-hydroxylamine

The title compound was prepared in substantially the same manner asdescribed in Example 2, step b, and was obtained as a clear oil.

Analysis for: C₂₃ H₂₃ F₃ N₂ O₃ Calc'd: C, 63.88; H, 5.36; N, 6.48 Found:C, 63.48; H, 5.33; N, 5.08

Step d)(E)-2-(1-methyl-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enyl}-[1,2,4]oxadiazolidine-3,5-dione

The title compound was prepared in substantially the same manner asdescribed in Example 2, step c, and was obtained as a white solid (0.31g, 27% yield, mp 55°-56° C.).

Analysis for: C₂₅ H₂₂ F₃ N₃ O₅ Calc'd: C, 59.88; H, 4.42; N, 8.38 Found:C, 60.14; H, 4.49; N, 8.32

Example 17(E)-2-(3-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-allyl)-[1,2,4]oxadiazolidine-3,5-dione

Step a)(E)-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-acrylicethyl ester

Triethylphosphonoacetate (4.38 ml, 22.06 mmol) was added dropwise in toa cold (0° C.) suspension of sodium hydride (0.59 g, 19.74 mmol) andtoluene (100 mL). After the addition, the mixture was stirred for 1hour, and then3-[5-methyl-2-(-4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy)-benzaldehyde(5.7 g, 15.79 mmol) in THF (20 ml) was added dropwise. The reactionmixture was stirred at room temperature for 1 hour, poured into water,acidified with HCl (2N), and extracted with EtOAc. The organic extractswere dried over MgSO₄. Evaporation and purification by flashchromatography on silica gel (hexane/EtOAc 5/1), gave a white solid (6.3g, 93% yield, m.p. 79°-80° C.).

Analysis for: C₂₃ H₁₈ F₃ N₃ O₅ Calc'd: C, 64.03; H, 4.67; N, 3.25 Found:C, 64.25; H, 4.63; N, 3.16

Step b)(E)-{3-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-prop-2-en-1-ol

The title compound was prepared in substantially the same manner asdescribed in Example 1, step d, and was obtained as a white solid, m.p.117°-118° C.

Analysis for: C₂₁ H₁₈ F₃ NO₃ Calc'd: C, 64.78; H, 4.66; N, 3.59 Found:C, 64.60; H, 4.54; N, 3.65

Step c)(E)-N-(3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]phenyl}-allyl)-hydroxylamine

The title compound was prepared in substantially the same manner asdescribed in Example 2, step b, and was obtained as a white solid, m.p.128°-130° C.

Analysis for: C₂₁ H₁₉ F₃ N₂ O₃ Calc'd: C, 62.37; H, 4.73; N, 6.93 Found:C, 62.17; H, 4.71; N, 6.79

Step d)(E)-2-(3-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-allyl)-[1,2,4]oxadiazolidine-3,5-dione

The title compound was prepared in substantially the same manner asdescribed in Example 1, step g, and was obtained as a white solid, m.p.179°-181° C.

Analysis for: C₂₃ H₁₈ F₃ N₃ O₅ Calc'd: C, 58.35; H, 3.83; N, 8.88 Found:C, 58.47; H, 3.70; N, 8.86

Example 18(E)-2-(2-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-cyclopropylmethyl)-1,2,4]oxadiazolidine-3,5-dione

(E)-2-(2-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-cyclopropylmethyl)-[1,2,4]oxadiazolidine-3,5-dione

Step a)(E)-2-{3-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-cyclopropyl)-methanol

Chloroiodomethane (3.37 mL, 46.28 mmol) was added dropwise in to a cold(0° C.) solution of diethyzinc (23.14 mL, 23.14 mmol) and dichloroethane(40 mL). After stirring for 10 minutes(E)-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-prop-2-en-1-ol(4.5 g, 11.57 mmol) in dichloromethane (10 mL) was added dropwise. Thereaction mixture was stirred for 1 hour, quenched with aqueous NH₄ Cland allowed to come to room temperature. After 15 minutes it was pouredinto water and extracted with ethyl ether. The organic extracts weredried over MgSO₄. Evaporation and purification by flash chromatographyon silica gel (hexane/EtOAc 3/2), gave a clear oil (2.8 g, 80% yield).

Analysis for: C₂₂ H₂₀ F₃ NO₃ Calc'd: C, 65.50; H, 5.00; N, 3.47 Found:C, 65.36; H, 5.12; N, 3.43

Step b)(E)-N-(2-{3-[5-methyl-2-(trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-cyclopropylmethyl)-hydroxylamine

The title compound was prepared in substantially the same manner asdescribed in Example 2, step b, and was obtained as a clear oil.

Analysis for: C₂₂ H₂₁ F₃ N₂ O₃ Calc'd: C, 63.15; H, 5.06; N, 6.69 Found:C, 62.90; H, 5.07; N, 6.66

Step c)(E)-2-(2-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-cyclopropylmethyl)-[1,2,4}oxadiazolidine-3,5-dione

The title compound was prepared in substantially the same manner asdescribed in Example 1, step g, and was obtained as a white solid, m.p.126°-128° C.

Analysis for: C₂₄ H₂₀ F₃ N₃ O₅ Calc'd: C, 59.14; H, 4.14; N, 8.62 Found:C, 59.27; H, 3.99; N, 8.78

Example 19(E)-2-(2-methyl-2-{3-[5-methyl-2-(4-trifluoromethoxy-phenyl)-oxazol-4-ylmethoxy]-phenyl}-cyclopropylmethyl)-[1,2,4}oxadiazolidine-3,5-dione

The title compound was prepared in substantially the same manner asdescribed in Example 17, and was obtained as a white solid, m.p. 42°-43°C.

Analysis for: C₂₅ H₂₂ F₃ N₃ O₆ Calc'd: C, 58.03; H, 4.28; N, 8.12 Found:C, 57.69; H, 4.32; N, 8.09

Example 20(E,E)-2-{5-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-hexa-2,4-dienyl}-[1,2,4]oxadiazolidine-3,5-dione

Step a)(E,E)-5-(3-[5-Methyl-2--phenyl-oxazol-4-ylmethoxy]-phenyl)-hexa-2,4-dienoicacid ethyl ester

Lithium bis(trimethylsilyl)amide (45.12 mL, 45.12 mmol) was addeddropwise in to a cold solution of triethyl 4-phosphonocrotonate (10.0ml, 45.12 mmol) in THF (200 mL). After stirring for 1 hour,1-(3-[5-methyl-2-phenyl-oxazol-4-ylmethoxy]-phenyl)-ethanone (12.0 g,39.1 mmol) in THF (50 mL) was added dropwise. The reaction mixture wasallowed to come to room temperature and stirred for 24 hours. Then, itwas quenched with aqueous NH₄ Cl, poured into water, acidified with HCL(2N), and extracted with EtOAc. The organic extracts were dried overMgSO₄. Evaporation and purification by flash chromatography on silicagel (hexane/EtOAc 8/1), gave a yellow oil (9.6 g, inseparable mixture ofcis- and trans-isomers).

Analysis for: C₂₅ H₂₅ NO₄ ×0.25 H₂ O Calc'd: C, 73.62; H, 6.26; N, 3.43Found: C, 73.69; H, 5.86; N, 3.44

Step b)(E,E)-5-[3-(5-Methyl-2--phenyl-oxazol-4-ylmethoxy]-phenyl)-hexa-2,4-dien-1-ol

Di-isobutyl aluminum hydride (1.0M in THF, 55.83 ml, 55.83 mmol) wasadded dropwise in to a cold (-50° C.) solution of(E,E)-5-(3-[5-methyl-2--phenyl-oxazol-4-ylmethoxy]-phenyl)-hexa-2,4-dienoicacid ethyl ester (7.5 g, 18.61 mmol, mixture of cis- and trans-isomers),THF (100 ml) and ethyl ether (100 mL). The reaction was warmed to 0° C.and stirred for 1 hour. The reaction mixture was quenched with acetone(dropwise addition), methanol, poured into water, acidified with HCl(2N), and extracted with EtOAc. The organic extracts were dried overMgSO₄. Evaporation and purification by flash chromatography on silicagel (hexane/EtOAc 4/1), gave the trans- (4.9 g), and the cis- (1.7 g)isomers as yellow oils.

(trans-) Analysis for: C₂₃ H₂₃ NO₃ Calc'd: C, 76.43; H, 6.41; N, 3.88Found: C, 76.25; H, 6.36; N, 4.03

(cis-) Analysis for: C₂₃ H₂₃ NO₃ Calc'd: C, 76.43; H, 6.41; N, 3.88Found: C, 75.98; H, 6.21; N, 3.69

Step c)(E,E)-N-(5-[3-(5-Methyl-2--phenyl-oxazol-4-ylmethoxy]-phenyl)-hexa-2,4-dienyl)-hydroxylamine

The title compound was prepared in substantially the same manner asdescribed in Example 2, step b, and was obtained as a light yellow oil.

Analysis for: C₂₃ H₂₄ N₂ O₃ Calc'd: C, 73.38; H, 6.43; N, 7.44 Found: C,73.41; H, 6.45; N, 7.20

Step d)(E,E)-2-{5-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-hexa-2,4-dienyl}-[1,2,4]oxadiazolidine-3,5-dione

The title compound was prepared in substantially the same manner asdescribed in Example 2, step c, and was obtained as a white solid, m.p.151°-152° C.

Analysis for: C₂₅ H₂₃ N₃ O₅ Calc'd: C, 67.40; H, 5.20; N, 9.43 Found: C,67.70; H, 5.28; N, 9.35

Example 21(Z,E)-2-{5-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-hexa-2,4-dienyl}-[1,2,4]oxadiazolidine-3,5-dione

The title compound was prepared in substantially the same manner asdescribed in Example 20, and was obtained as a white solid, m.p.117°-118° C.

Analysis for: C₂₅ H₂₃ N₃ O₅ Calc'd: C, 67.40; H, 5.20; N, 9.43 Found: C,67.32; H, 5.21; N, 9.32

Example 222-(1-methyl-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-prop-2-ynyl)-[1,2,4]oxadiazolidine-3,5-dione

Step a)4-(3-Ethynyl-phenoxymethyl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole

(Bromomethyl)triphenylphosphonium bromide (21.2 g, 48.61 mmol) was addedportionwise to a -78° C. mixture of potassium-tert-butoxide (10.9 g,97.23 mmol) in THF (200 mL). The mixture was stirred for 2 h, then3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzaldehyde(11.7 g, 32.41 mmol) in THF (50 mL) was added dropwise. The mixture wasstirred for 1 hour at -78° C., then at room temperature for 2 days. Thereaction mixture was quenched with aqueous NH₄ Cl, poured into water,acidified with HCl (2N), and extracted with EtOAc. The organic extractswere dried over MgSO₄. Evaporation and purification by flashchromatography on silica gel (hexane/EtOAc 8/1) gave a white solid (7.5g, 67% yield, mp 62°-64° C.).

Analysis for: C₂₀ H₁₄ F₃ NO₂ ×0.25 H₂ O Calc'd: C, 66.39; H, 4.01; N,3.87 Found: C, 66.67; H, 3.75; N, 4.15

Step b)4-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-3-yn-2-ol

Lithium bis(trimethylsilyl)amide (10.5 mL, 10.5 mmol) was added to acold (0° C.) solution of4-(3-ethynyl-phenoxymethyl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole(3.0 g, 8.77 mmol) in THF (100 mL). After 1 h at 0° C., acetaldehyde(0.59 mL, 10.5 mmol) was added dropwise. The mixture was stirred for 30min, then quenched with aqueous NH₄ Cl, poured into water, acidifiedwith HCl (2N), and extracted with EtOAc. The organic extracts were driedover MgSO₄. Evaporation and purification by flash chromatography onsilica gel(hexane/EtOAc 4/1) gave a yellow solid (2.1 g, 59% yield, m.p.86°-87° C.).

Analysis for: C₂₂ H₁₈ F₃ NO₃ Calc'd: C, 65.83; H, 4.52; N, 3.49 Found:C, 65.89; H, 4.38; N, 3.36

step c)N-(1-Methyl-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-prop-2-ynyl)-hydroxylamine

The title compound was prepared in substantially the same manner asdescribed in Example 2, step b, and was obtained as a light yellowsolid, m.p. 110°-112° C.

Analysis for: C₂₂ H₁₉ F₃ N₂ O₃ Calc'd: C, 63.46; H, 4.60; N, 6.73 Found:C, 66.71; H, 4.56; N, 6.69

Step d)2-(1-methyl-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-prop-2-ynyl)-[1,2,4]oxadiazolidine-3,5-dione

The title compound was prepared in substantially the same manner asdescribed in Example 1, step g, and was obtained as a white solid, m.p.84°-86° C.

Analysis for: C₂₄ H₁₈ F₃ N₃ O₅ Calc'd: C, 59.38; H, 3.74; N, 8.66 Found:C, 59.38; H, 3.50; N, 8.56

Example 232-{1-methyl-3-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-prop-2-ynyl}-[1,2,4]oxadiazolidine-3,5-dione

The title compound was prepared in substantially the same manner asdescribed in Example 21, and was obtained as a white solid, m.p. 55°-57°C.

Analysis for: C₂₃ H₁₉ N₃ O₅ ×0.25 H₂ O Calc'd: C, 65.40; H, 4.01; N,9.95 Found: C, 65.20; H, 4.36; N, 10.23

Example 24(E)-5-{3-[3-(5-methyl-2-phenyl-oxazol-4-ylmethyl]-phenyl]-but-2-enyl}-oxazolidine-2,4-dione

Step a)(E)-4-[3-(3-Chloro-1-methyl-propenyl)-phenoxymethyl]-5-methyl-2-phenyl-oxazole

3-[3-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-but-2-en-1-ol (10.0g, 29.85 mmol) in ether (50 mL) was added to a cold (0° C.) suspensionof phosphorus oxychloride (9.31 g, 44.77 mmol), calcium carbonate (4.47g, 44.77 mmol), and ether (300 mL). After 30 minutes, the reactionmixture was poured into water. The organic layer was separated, washedwith water and brine. The organic extracts were dried over MgSO₄.Evaporation and purification by flash chromatography on silica gel(hexane/EtOAc 5/1) gave a clear oil (9.1 g, 86% yield).

Analysis for: C₂₁ H₂₀ ClNO₂ Calc'd: C, 71.28; H, 5.70; N, 3.96 Found: C,71.42; H, 5.71; N, 3.88

Step b)(E)-5-{3-[3-(5-methyl-2-phenyl-oxazol-4-ylmethyl]-phenyl]-but-2-enyl}-oxazolidine-2,4-dione

Tert-butyl lithium (17.5 mL, 29.7 mmol) was added dropwise in to arapidly stirred cold (-78° C.) solution of lithium chloride (3.6 g,84.84 mmol) and oxazolidine-2,4-dione (1.43 g, 14.14 mmol) in THF (90mL). The mixture was stirred at -78° C. for 30 minutes, then graduallywarmed to 0° C. After recooling to -78° C.,(E)-4-[3-(3-chloro-1-methyl-propenyl)-phenoxymethyl]-5-methyl-2-phenyl-oxazole(5.0 g, 14.14 mmol) in THF (5 mL) was added all at once. After stirringfor 10 minutes at -78° C., the mixture was gradually warmed to roomtemperature, and allowed to stir for 5 hours. Then, the reaction mixturewas quenched with aqueous NH₄ Cl, poured into water, acidified with HCl,and extracted with EtOAc. The organic extracts were dried over MgSO₄.Evaporation and purification by flash chromatography on silica gel(hexane/EtOAc 3/1), gave a white solid (3.5 g, 59% yield, m.p. 138°-139°C.).

Analysis for: C₂₄ H₂₂ N₂ O₅ Calc'd: C, 68.89; H, 5.30; N, 6.69 Found: C,68.49; H, 5.29; N, 6.71

Example 25(E)-5-[3-(3-{5-methyl-2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-oxazol-4-ylmethoxy}-phenyl)-but-2-enyl]-oxazolidine-2,4-dione

The title compound was obtained in substantially the same manner asdescribed in Example 24, and was obtained as a white solid, m.p.120°-121° C.

Analysis for: C₂₆ H₂₃ F₃ N₂ O₆ Calc'd: C, 60.46; H, 4.49; N, 5.42 Found:C, 60.62; H, 4.47; N, 5.18

Example 26(E)-5-(3-{3-[5-methyl-2-(4-trifluoromethoxy-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enyl)-oxazolidine-2,4-dione

The title compound was obtained in substantially the same manner asdescribed in Example 24, and was obtained as a white solid, m.p.105°-106° C.

Analysis for: C₂₅ H₂₁ F₃ N₂ O₆ Calc'd: C, 59.76; H, 4.21; N, 5.58 Found:C, 59.92; H, 4.12; N, 5.54

Example 27(E)-5-(3-{3-[2-(5-methyl-2--phenyl-oxazol-4-yl)-ethoxy]-phenyl}-but-2-enyl)-oxazolidine-2,4-dione

The title compound was obtained in substantially the same manner asdescribed in Example 24, and was obtained as a white solid, m.p.100°-101° C.

Analysis for: C₂₅ H₂₄ N₂ O₅ Calc'd: C, 69.43; H, 5.59; N, 6.48 Found: C,69.59; H, 5.89; N, 6.16

Example 28(E)-5-{3-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-but-2-enyl}-thiazolidine-2,4-dione

Butyl lithium (16.6 mL, 41.58 mmol) was added dropwise in to a cold(-78° C.) solution of thiazolidine-2,4-dione (2.31 g, 19.8 mmol) and THF(80 mL). The mixture was stirred at -78° C. for 15 minutes, thengradually warmed to 0° C., and stirred for 30 minutes to complete thedianion formation. After recooling to -78° C.,4-[3-(3-chloro-1-methyl-propenyl)-phenoxymethyl]-5-methyl-2-phenyl-oxazole(7.0 g, 19.8 mmol) in THF (15 mL) was added all at once. After stirringfor 30 minutes at -78° C., the mixture was gradually warmed to roomtemperature, and allowed to stir for 2 hours. Then, the reaction mixturewas quenched with aqueous NH₄ Cl, poured into water, acidified with HCl,and extracted with EtOAc. The organic extracts were dried over MgSO₄.Evaporation and purification by flash chromatography on acid washed (5%H₃ PO₄ /MeOH) silica gel (hexane/EtOAc 3/1), gave a white solid (2.9 g,33% yield, m.p. 48°-49° C.).

Analysis for: C₂₄ H₂₂ N₂ O₄ S×0.25 H₂ O Calc'd: C, 65.68; H, 5.13; N,6.38 Found: C, 65.72; H, 5.19; N, 6.45

Example 29(E)-5-(3-{3-[5-methyl-2-(4-trifluoromethoxy-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enyl)-thiazolidine-2,4-dione

The title compound was obtained in substantially the same manner asdescribed in Example 27, and was obtained as a light yellow solid, m.p.50°-51° C.

Analysis for: C₂₅ H₂₁ F₃ N₂ O₅ S Calc'd: C, 57.91; H, 4.08; N, 5.40Found: C, 57.57; H, 4.16; N, 5.30

Example 30(E)-2-(3-{3-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enyl)-[1,2,4]-thiadiazolidine-3,5-dione

Step a) 4,5-Dimethyl-2-(4-trifluoromethyl-phenyl)-oxazole N-oxidehydrochloride

HCl gas (21.2 g, 58.1 mmol) was bubbled via syringe into a 0° C.solution of 4-trifluoromethylbenzaldehyde (50 g, 28.7 mmol),2,3-butanedione monoxime (26.40 g, 26.1 mmol), and EtOAc (105 ml). Thereaction was stirred at 5° C. for 3 h. Ice cold ether (575 ml) was thenadded, and the resultant precipitate was filtered, washed with ether,and dried at 25° C. for 16 h to give the product as a white solid (54.79g, 71% yield, mp 149°-159° C.).

Analysis for: C₁₂ H₁₁ ClF₃ NO₂ Calc'd: C, 49.08; H, 3.77; N, 4.77 Found:C, 49.48; H, 3.81; N, 4.88

Step b) 4-Chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole

In to a 5° C. solution of4,5-dimethyl-2-(4-trifluoromethyl-phenyl)-oxazole N-oxide hydrochloride(113.71 g, 387.5 mmol) in CHCl₃ (560 ml), was added phosphorusoxychloride (39.4 ml, 422.4 mmol) in CHCl₃, dropwise over 15 min. Thereaction was refluxed for 2.5 h, then cooled to 5° C., poured into icewater, and basified with NaOH (1N). The organic layer was dried overMgSO₄. Evaporation and recrystallization from ether/hexane, gave ayellow solid (30.0 g, 28% yield, mp 84°-85° C.).

Analysis for: C₁₂ H₉ ClF₃ NO Calc'd: C, 52.29; H, 3.29; N, 5.08 Found:C, 52.54; H, 3.20; N, 4.92

Step c)1-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-ethanone

A mixture of4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole (24.3 g,88.2 mmol), 3-hydroxyacetophenone (10.0 g, 73.5 mmol), and potassiumcarbonate (13.2 g, 95.6 mmol), was stirred at 70° C. for 16 h. Thereaction was poured into water, acidified with HCl (1N), and extractedwith EtOAc. The organic extracts were dried over MgSO₄. Evaporation andpurification by flash chromatography on silica gel (hexane/EtOAc 9/1),gave an off-white solid (20.14 g, 60% yield, mp 90°-91° C.).

Analysis for: C₂₀ H₁₆ F₃ NO₃ Calc'd: C, 63.99; H, 4.29; N, 3.73 Found:C, 63.86; H, 4.30; N, 3.64

Step d)(E)-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enoicacid ethyl ester

In to a 0° C. mixture of sodium hydride (4.27 g, 142.6 mmol) and toluene(500 ml), was added triethylphosphonoacetate (29.79 ml, 150.1 mmol) viasyringe. The reaction was stirred for 1 hour, and then1-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-ethanone(28.15 g, 75.1 mmol) in THF (150 ml) was added dropwise. The reactionmixture was stirred at room temperature for 16 h, poured into water,acidified with HCl (2N), and extracted with EtOAc. The organic extractswere dried over MgSO₄. Evaporation and purification by flashchromatography on silica gel (hexane/EtOAc 20/1) gave a white solid(24.42 g, 73% yield, mp 91°-92° C.).

Analysis for: C₂₄ H₂₃ F₃ NO₄ Calc'd: C, 64.57; H, 5.19; N, 3.14 Found:C, 64.81; H, 5.01; N, 3.13

Step e)(E)-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-en-1-ol

Di-isobutyl aluminum hydride (1.0M in THF) (219.2 ml, 219.2 mmol) wasadded, by syringe, to a -25° C. solution of3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enoicacid ethyl ester (24.42 g, 54.8 mmol) in THF (300 ml). The reaction waswarmed to 0° C. and stirred for 1.5 h. It was poured into ice water,acidified with HCl (2N), stirred for 45 min, then extracted with EtOAc.The organic extracts were dried over MgSO₄. Evaporation and purificationby flash chromatography on silica gel (hexane/EtOAc 3/1), gave a lightyellow solid (17.68 g, 82% yield, mp 145°-146° C.).

Analysis for: C₂₂ H₁₈ F₃ NO₃ Calc'd: C, 65.83; H, 4.52; N, 3.49 Found:C, 65.78; H, 4.53; N, 3.45

Step f)(E)-4-[3-(3-Chloro-1-methyl-propenyl)-phenoxymethyl]-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole

(E)-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-en-1-ol(6.0 g, 14.9 mmol) in ether (50 mL) was added to a cold (0° C.)suspension of phosphorus oxychloride (4.4 g, 20.84 mmol), calciumcarbonate (1.5 g, 14.9 mmol), and ether (50 mL). After 30 minutes, thereaction mixture was poured into water. The organic layer was separated,washed with water and brine. The organic extracts were dried over MgSO₄.Evaporation and purification by flash chromatography on silica gel(hexane/EtOAc 20/1) gave a clear oil (2.1 g, 35% yield).

Step g)(E)-3-{3-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-ylmethoxy]phenyl}-but2-enylamine

A mixture of(E)-4-[3-(3-Chloro-1-methyl-propenyl)-phenoxymethyl]-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole(5.0 g, 11.86 mmol), sodium azide (2.31 g, 35.6 mmol) and DMF (100 mL)was stirred at 80° C. for 18 hours. The reaction mixture was poured intowater (200 mL), acidified to pH=3 with HCL (2N), and extracted withEtOAc. The organic extracts were dried over MgSO₄. Evaporation gave abrown oil (4.3 g), which was dissolved in THF (100 mL) and cooled to 0°C. Lithium aluminum hydride (5.5 mL, 1.0M, 5.5 mmol) was added dropwiseover a 20 minutes period. The reaction mixture was quenched with EtOAc(20 mL) and NaOH (100 mL, 2.5N), and extracted with ethyl ether. Theorganic extracts were dried over MgSO₄. Evaporation and purification byflash chromatography on silica gel (eluting solvent EtOAc:MeOH 1:1) gavea yellow oil (2.0 g, 42% yield). MS (m/e): 402 (M+).

Step h)(E)-3-{3-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-ylmethoxy]-phenyl}-but-2-enyl)-urea

Trimethylsilylisocyanate (1.35 mL. 9.95 mmol) was added dropwise to asolution of(E)-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-ylmethoxy]-phenyl}-but-2-enylamine(2.0 g, 4.97 mmol) in dioxane (75 mL). The reaction mixture was stirredfor 18 hours, and poured into mixture of water (100 mL) and saturatedammonium chloride (100 mL). The aqueous layer was extracted with EtOAc,and the organic extracts were dried over MgSO₄. Evaporation andpurification by flash chromatography on silica gel (eluting solventEtOAc:EtOH 1:1) gave a white solid (1.2 g, 55% yield). MS (m/e): 445(M+).

Analysis for: C₂₃ H₂₂ F₃ N₃ O₃ Calc'd: C, 62.02; H, 4.98; N, 9.43 Found:C, 61.25; H, 4.63; N, 9.28

Step i)(E)-2-(3-{3-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enyl)-[1,2,4]-thiadiazolidine-3,5-dione

Chlorocarbonylsulfenyl chloride (0.54 mL, 6.4 mmol) was added dropwiseinto a mixture of(E)-3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-ylmethoxy]-phenyl}-but-2-enyl)-urea(2.2 g, 4.94 mmol) and toluene (40 mL). The reaction mixture was heatedto 60° C. for 4 hours, poured into water, acidified with HCl (2N) andextracted with EtOAc. The organic extracts were dried over MgSO₄.Evaporation and purification by flash chromatography on acidic silicagel (MeOH/H₃ PO₄, eluting solvent EtOAc:hexane 1:3) gave an off-whitesolid (0.63 g, 25 5 yield; m.p. 60°-61° C.).

Analysis for: C₂₄ H₂₀ F₃ N₃ O₄ S Calc'd: C, 57.25; H, 4.00; N, 8.35Found: C, 56.94; H, 3.97; N, 8.21

Pharmacology

Determination of Blood Glucose Lowering in db/db Mice

On the morning of Day 1, 35 mice [male diabetic db/db (C57BL/KsJ) mice(Jackson Laboratories), 2-7 months of age and 50-70 g] were fasted for 4hours, weighed and a baseline blood sample (15-30 μl) was collected fromthe tail-tip of each mouse without anesthesia, and placed directly intoa fluoride-containing tube, mixed and maintained on ice. Food was thenreturned to the mice. The plasma was separated and levels of glucose inplasma determined by the Abbott VP Analyzer. Because of the variableplasma glucose levels of the db/db mice, 5 mice having the most extreme(i.e., highest or lowest) plasma glucose levels were excluded and theremaining 30 mice were randomly assigned into 7 groups of equivalentmean plasma glucose levels (N=6 for vehicle and N=4 for each druggroup). On the afternoon of Days 1, 2 and 3, the vehicle, control ortest drugs were administered (p.o.) to the ad libitum fed mice. On themorning of Day 4, the mice were weighed and food removed, but water wasavailable ad libitum. Three hours later, a blood sample was collectedand then the mice were given the fourth administration of drug orvehicle. Blood samples were collected again from the unanesthetized miceat 2 and 4 hrs after drug administration. The plasma was separated andlevels of glucose in plasma was determined by the Abbott VP Analyzer.

For each mouse, the percent change of its plasma glucose level on Day 4(mean of the 2 and 4 hr samples) from respective level before drugadministration (Day 1 baseline sample) is determined as follows:##EQU1##

Analysis of variance followed by Dunnett's multiple comparison(one-sided) will be used to estimate the degree of statisticalsignificance of the difference between the vehicle control group and theindividual drug-treated groups. A drug will be considered active, at thespecific dosage administered, if the difference of the plasma glucoselevel has a p<0.05. The actual difference between the mean percentchange of the vehicle and drug-treated groups is shown in Table 1.

The positive control, ciglitazone produces a 18 to 34% decrease inplasma glucose levels at 100 mg/kg/day×4 days, p.o.

                  TABLE 1                                                         ______________________________________                                                                 db/db data                                           Compound of    Dose      % Change                                             Example No.    mg/kg, p.o.                                                                             glucose                                              ______________________________________                                        1              100       -76                                                  2              100       -78                                                  3              100       -71                                                  4              100       -45                                                  5              100       -47                                                  6              100       -33                                                  7              100       -50                                                  9              100       -47                                                  10             100       -47                                                  11             100       -30                                                  12             100       -50                                                  16             100       -20                                                  18             100       -38                                                  21             50        -32                                                  24             100       -23                                                  25             100       -49                                                  ______________________________________                                         References:                                                                   1. Coleman, D. L. (1982) Diabetesobesity syndromes in mice. Diabetes 31       (Suppl. 1); 1-6.                                                              2. Tutwiler, G. F., T. Kirsch, and G. Bridi (1978). A pharmacologic           profile of McN3495                                                            [N(1-methyl-2-pyrrolidinylidene)-Nphenyl-1-pyrrolidine-carboximidamide],      new, orally effective hypoglycemic agent. Diabetes 27: 856-857.               3. Lee, S. M., G. Tutwiler, R. Bressler, and C. H. Kircher (1982).            Metabolic control and prevention of nephropathy by 2tetradecylglycidate i     the diabetic mouse (db/db). Diabetes 31: 12-18.                               4. Chang, A. Y., B. W. Wyse, B. J. Gilchrist, T. Peterson, and R. Diani       (1983) Ciglitazone, a new hypoglycemic agent. 1. Studies in ob/ob and         db/db mice, diabetic Chinese hamsters, and normal and streptozocindiabeti     rats. Diabetes 32: 830-838.                                                   5. Hosokawa, T., K. Ando, and G. Tamura (1985). An ascochlorin derivative     AS6, reduces insulin resistance in the genetically obese diabetic mouse,      db/db. Diabetes 34: 267-274.                                             

Determination of Blood Glucose Lowering Effect in ob/ob mice

The non-insulin-dependent diabetic syndrome can be typicallycharacterized by obesity, hyperglycemia, abnormal insulin secretion,hyperinsulinemia and insulin resistance. The geneticallyobese-hyperglycemic ob/ob mouse exhibits many of these metabolicabnormalities and is thought to be a useful media to search forhypoglycemic agents to treat NIDDM (Coleman, 1978)

Male or female ob/ob mice (C57B1/6J), ages 2 to 5 months (10 to 65 g),of a similar age are randomized according to plasma glucose into 4groups of 10 mice. The mice are housed 5 per cage and are maintained onnormal rodent chow with water ad libitum. The mice receive test compounddaily. The test compound is suspended in 0.5 mL of 0.5% methyl celluloseand is administered by gavage (dissolved in drinking water) or admixedin the diet. The dose of compound given ranges from 2.5 to 200mg/kg/day. Body weight of fed animals is measured at the beginning ofeach week and doses for the entire week are calculated using this weightand are expressed in terms of the active moiety of the compound. Controlmice receive vehicle only.

On the morning of Days 4, 7 or 14 two drops of blood (approximately 50μl) are collected into sodium fluoride containing tubes either from thetail vein or after decapitation. For those studies in which the compoundis administered daily by gavage, the blood samples are collected fourhour after compound administration. The plasma is isolated bycentrifugation and the concentration of glucose is measuredenzymatically on an Abbott V. P. Analyzer and the plasma concentrationof insulin is determined by radioimmunoassay (Heding, 1972). For eachmouse, the percentage change in plasma glucose on Day 4, 7 or 14 iscalculated relative to the mean plasma glucose of the vehicle treatedmice. Analysis of variance followed by Dunnett's Comparison Test (onetailed) is used to estimate the significant difference between theplasma glucose values from the control group and the individual compoundtreated groups. The results are presented in Table II.

The diabetic db/db (C57BL/KsJ) mouse exhibits many metabolicabnormalities that are associated with non-insulin dependent diabetesmellitus (Type II) in humans. The animals are obese, glucose intolerantand have fasting hyperglycemia which is sometimes accompanied by aparadoxical hyperinsulinemia (1). Furthermore, the db/db mouse willeventually develop some of the long-term complications that have beenassociated with diabetes mellitus (1). In spite of these commonalities,the acute administration of sulfonylureas (even at extremely high doses)will not reduce the hyperglycemia of the db/db mouse (2). The ability ofa few other hypoglycemic agents to be effective in this species suggestthat the other agents have mechanism of action which are different fromthat of the sulfonylureas (2,3,4,5). Such compounds, therefore, are morelikely to be efficacious in the population of type II diabetic patientsthat do not respond to sulfonylurea therapy.

                  TABLE II                                                        ______________________________________                                                         ob/ob data                                                   Compound of                                                                              Dose        % Change  % Change                                     Example No.                                                                              mg/kg, p.o. glucose   insulin                                      ______________________________________                                        4          100         -39       -82                                          6          100         -39       -76                                          7          100         -30       -75                                          10         100         -36       -28                                          22         100         -32       -91                                          30         100         -29       -26                                          ______________________________________                                         References:                                                                   1. Brichard, S., Bailey, C. and Henquin, J.: Marked improvement of glucos     homeostasis in diabetic ob/ob mice given oral vanadate. Diabetes 39:          1326-1332, 1990.                                                              2. Chang, A., Wyse, B., Gilchrist, B., Peterson, T. and Diani, A.:            Ciglitazone, a new hypoglycemic agent. I. Studies in ob/ob and db/db mice     diabetic Chinese hamsters, and normal and streptozoticininduced diabetic      rats. Diabetes 32: 830-838, 1983.                                             3. Coleman, D.: Obese and diabetes: Two mutant genes causing                  diabetesobesity syndromes in mice. Diabetologia 14: 141-148, 1978.            4. Heding, L. G.: Determination of total serum insulin (IRI) in               insulintreated diabetic patients. Diabetologia 8: 260-266, 1972.         

Pharmaceutical Composition

Based on the results of the pharmacological assay, the compounds of thisinvention are useful in the treatment of hyperglycemia in diabetesmellitus.

The compounds may be administered neat or with a pharmaceutical carrierto a mammal in need thereof. The pharmaceutical carrier may be solid orliquid and the active compound shall be a therapeutically effectiveamount.

A solid carrier can include one or more substances which may also act asflavoring agents, lubricants, solubilizers, suspending agents, fillers,glidants, compression aids, binders or tablet-disintegrating agents; itcan also be an encapsulating material. In powders, the carrier is afinely divided solid which is in admixture with the finely dividedactive ingredient. In tablets, the active ingredient is mixed with acarrier having the necessary compression properties in suitableproportions and compacted in the shape and size desired. The powders andtablets preferably contain up to 99% of the active ingredient. Suitablesolid carriers include, for example, calcium phosphate, magnesiumstearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose,methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine,low melting waxes and ion exchange resins.

Liquid carriers are used in preparing solutions, suspensions, emulsions,syrups, elixirs and pressurized compositions. The active ingredient canbe dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fats. The liquid carrier can containother suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid carriers fororal and parenteral administration include water (partially containingadditives as above, e.g. cellulose derivatives, preferably sodiumcarboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g. glycols) and their derivatives,and oils (e.g. fractionated coconut oil and arachis oil). For parenteraladministration, the carrier can also be an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid carriers are useful insterile liquid form compositions for parenteral administration. Theliquid carrier for pressurized compositions can be halogenatedhydrocarbon or other pharmaceutically acceptable propellent.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. The compound can also be administered orallyeither in liquid or solid composition form.

Preferably, the pharmaceutical composition is in unit dosage form, e.g.as tablets or capsules. In such form, the composition is sub-divided inunit dose containing appropriate quantities of the active ingredient;the unit dosage forms can be packaged compositions, for example,packeted powders, vials, ampoules, prefilled syringes or sachetscontaining liquids. The unit dosage form can be, for example, a capsuleor tablet itself, or it can be the appropriate number of any suchcompositions in package form. A dosage range of from 0.1 to 200mg/kg/day is contemplated, with a preferred dosage of from 0.1 to 100mg/kg/day. Due to uncertainty in relating laboratory mouse study data toother mammals, the degree of hyperglycemia, and the compound selected,the dosages used in the treatment of non-insulin dependent diabetesmellitus must be subjectively determined by a physician or veterinarianaccording to standard medical or veterinary practice.

What is claimed is:
 1. A compound according to formula I below ##STR32##wherein: R¹ is C₁ -C₆ alkyl, C₃ -C₈ cycloalkyl, thienyl, furyl, pyridyl,##STR33## where R¹⁰ is hydrogen, C₁ -C₆ alkyl, fluorine, chlorine,bromine, iodine, C₁ -C₆ alkyoxy, trifluoroalkyl or trifluoroalkoxy;R² ishydrogen or C₁ -C₆ alkyl; X is O or S; n is 1 or 2; A is ##STR34## whereR³ is hydrogen, C₁ -C₆ alkyl, halogen, C₁ -C₆ alkoxy, trifluoroalkyl ortrifluoroalkoxy; B is ##STR35## where R⁴ is hydrogen, C₁ -C₆ alkyl,allyl, C₆ -C₁₀ aryl, C₆ -C₁₀ aryl-(CH₂)₁₋₆ --, fluorine, chlorine,bromine, iodine, trimethylsilyl or C₃ -C₈ cycloalkyl;R⁵ is hydrogen, C₁-C₆ alkyl, C₆ -C₁₀ aryl, or C₆ -C₁₀ aryl-(CH₂)₁₋₆ --; m is 0, 1, or 2;R⁶ is hydrogen or C₁ -C₆ alkyl; R⁷ is hydrogen or C₁ -C₆ alkyl; R⁸ andR⁹ are selected independently from hydrogen, C₁ -C₆ alkyl, fluorine,chlorine, bromine, or iodine; Y is S; Z is N or CH; or apharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1 which has the formula Ia ##STR36## where: R¹⁰ is hydrogen, C₁-C₆ alkyl, fluorine, chlorine, bromine, iodine, C₁ -C₆ alkoxy,trifluoroalkyl or trifluoroalkoxy;n is 1 or 2; A is ##STR37## B is##STR38## where m is 0, 1 or 2; R⁴, R⁵, R⁶, and R⁷ are independentlyhydrogen or C₁ -C₆ alkyl; Y is S; Z is N or CH; or a pharmaceuticallyacceptable salt thereof.
 3. A compound according to claim 2 which hasthe formula Ib ##STR39## wherein: R¹⁰ is hydrogen, CF₃ --, CF₃ O--, CF₃CH₂ -- or Cl--;n is 1 or 2; A is ##STR40## B is ##STR41## wherein m is 0or 1; R⁴, R⁵, R⁶, and R⁷ are independently hydrogen, methyl or ethyl; Yis S; Z is N or CH; or a pharmaceutically acceptable salt thereof.
 4. Acompound according to claim 3 which is selected from the groupconsistingof:(E)-5-{3-[3-(5-methyl-2-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enyl)-thiazolidine-2,4-dione,(E)-5-(3-{3-[5-methyl-2-(4-trifluoromethoxy-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enyl)-thiazolidine-2,4-dione,and(E)-2-(3-{3-[5-methyl-2-(4-trifluoromethoxy-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enyl)-[1,2,4]thiadiazolidine-3,5-dione.5. A method of treating hyperglycemia of non-insulin dependent diabetesmellitus in mammals which comprises administration thereto of atherapeutically effective amount of a compound of formula I ##STR42##wherein: R¹ is C₁ -C₆ alkyl, C₃ -C₈ cycloalkyl, thienyl, furyl, pyridyl,##STR43## where R¹⁰ is hydrogen, C₁ -C₆ alkyl, fluorine, chlorine,bromine, iodine, C₁ -C₆ alkyoxy, trifluoroalkyl or trifluoroalkoxy;R² ishydrogen or C₁ -C₆ alkyl; X is O or S; n is 1 or 2; A is ##STR44## whereR³ is hydrogen, C₁ -C₆ alkyl, halogen, C₁ -C₆ alkoxy, trifluoroalkyl ortrifluoroalkoxy; B is ##STR45## where R⁴ is hydrogen, C₁ -C₆ alkyl,allyl, C₆ -C₁₀ aryl, C₆ -C₁₀ aryl-(CH₂)₁₋₆ --, fluorine, chlorine,bromine, iodine, trimethylsilyl or C₃ -C₈ cycloalkyl;R⁵ is hydrogen, C₁-C₆ alkyl, C₆ -C₁₀ aryl, or C₆ -C₁₀ aryl-(CH₂)₁₋₆ --; m is 0, 1, or 2;R⁶ is hydrogen or C₁ -C₆ alkyl; R⁷ is hydrogen or C₁ -C₆ alkyl; R⁸ andR⁹ are selected independently from hydrogen, C₁ -C₆ alkyl, fluorine,chlorine, bromine, or iodine; Y is S; Z is N or CH; or apharmaceutically acceptable salt thereof.
 6. A method of treatmentaccording to claim 5 wherein the compound used has the formula Ia##STR46## where: R¹⁰ is hydrogen, C₁ -C₆ alkyl, fluorine, chlorine,bromine, iodine, C₁ -C₆ alkoxy, trifluoroalkyl or trifluoroalkoxy;n is 1or 2; A is ##STR47## B is ##STR48## where m is 0, 1 or 2; R⁴, R⁵, R⁶,and R⁷ are independently hydrogen or C₁ -C₆ alkyl; Y is S; Z is N or CH;or a pharmaceutically acceptable salt thereof.
 7. A method of treatmentaccording to claim 6 wherein the compound used has the formula Ib##STR49## wherein: R¹⁰ is hydrogen, CF₃ --, CF₃ O--, CF₃ CH₂ O-- orCl--;n is 1 or 2; A is ##STR50## B is ##STR51## wherein m is 0 or 1; R⁴,R⁵, R⁶, and R⁷ are independently hydrogen, methyl or ethyl; Y is S; Z isN or CH; or a pharmaceutically acceptable salt thereof.
 8. A method oftreatment according to claim 7 wherein the compound used is selectedfrom the group consistingof:(E)-5-{3-[3-(5-methyl-2-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enyl)-thiazolidine-2,4-dione,(E)-5-(3-{3-[5-methyl-2-(4-trifluoromethoxy-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enyl)-thiazolidine-2,4-dione,and(E)-2-(3-{3-[5-methyl-2-(4-trifluoromethoxy-phenyl)-oxazol-4-ylmethoxy]-phenyl}-but-2-enyl)-[1,2,4]thiadiazolidine-3,5-dione.9. A pharmaceutical composition for the treatment of hyperglycemia inmammals comprising a pharmaceutical carrier and a therapeuticallyeffective amount of a compound having the formula: ##STR52## wherein: R¹is C₁ -C₆ alkyl, C₃ -C₈ cycloalkyl, thienyl, furyl, pyridyl, ##STR53##where R¹⁰ is hydrogen, C₁ -C₆ alkyl, fluorine, chlorine, bromine,iodine, C₁ -C₆ alkyoxy, trifluoroalkyl or trifluoroalkoxy;R² is hydrogenor C₁ -C₆ alkyl; X is O or S; n is 1 or 2; A is ##STR54## where R³ ishydrogen, C₁ -C₆ alkyl, halogen, C₁ -C₆ alkoxy, trifluoroalkyl ortrifluoroalkoxy; B is ##STR55## where R⁴ is hydrogen, C₁ -C₆ alkyl,allyl, C₆ -C₁₀ aryl, C₆ -C₁₀ aryl-(CH₂)₁₋₆ --, fluorine, chlorine,bromine, iodine, trimethylsilyl or C₃ -C₈ cycloalkyl;R⁵ is hydrogen, C₁-C₆ alkyl, C₆ -C₁₀ aryl, or C₆ -C₁₀ aryl-(CH₂)₁₋₆ --; m is 0, 1, or 2;R⁶ is hydrogen or C₁ -C₆ alkyl; R⁷ is hydrogen or C₁ -C₆ alkyl; R⁸ andR⁹ are selected independently from hydrogen, C₁ -C₆ alkyl, fluorine,chlorine, bromine, or iodine; Y is S; Z is N or CH; or apharmaceutically acceptable salt thereof.